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表皮生長因子接受體(EGFR)突變呈現陽性的非小細胞肺癌病患要較那些突變呈現陰性的病患有更佳的生存優勢
2010年第35屆歐洲癌症醫學會大會所發表的標靶藥物愛瑞莎泛亞洲地區臨床研究(IPASS)，結果顯示帶有表皮生長因子接受體突變的非小細胞肺癌患者，無論是接受愛瑞莎標靶治療或者是卡鉑(carboplatin)/太平洋紫杉醇(paclitaxel)化療，在整體生存期(Overall Survival, OS)方面均有較佳的反應。
愛瑞莎目前已被美國核淮於治療曾接受第一線化療但失敗的局部惡化或轉移的非小細胞肺癌病患，去年(2009)愛瑞莎也被歐洲委員會核淮於治療曾接受治療且帶有表皮生長因子接受體突變的局部惡化或轉移的非小細胞肺癌病患。
這項泛亞洲臨床研究結果顯示，愛瑞莎標靶治療與使用卡鉑/太平洋紫杉醇化療的患者，雖然在無惡化生存期(Progression-Free Survival)能獲得明顯的改善，但全體病患的整體生存期中位數比較上，兩者間卻無明顯的差異。(使用愛瑞莎的病患是18.8個月，而接受化療的病患是17.4個月。HR, 0.90, 95%, CI, 0.79 - 1.02; P = .11)。
如以病患是否帶有表皮生長因子接受體突變作為區份。在整體生存期中位數上，表皮生長因子接受體突變的非小細胞肺癌病患，接受愛瑞莎治療者中位數為21.6個月，而接受化療的病患，整體生存期中位數為21.9個月。(HR, 1.002; 95% CI, 0.756 - 1.328; P = .990)。而不帶有表皮生長因子接受體突變的非小細胞肺癌病患，接受愛瑞莎標靶治療其整體生存期中位數為11.2個月，而接受化療的病患為12.7個月。(HR, 1.181; 95% CI, 0.857 - 1.628; P = .309)。
台大醫院癌症研究中心主任楊志新醫師表示，雖然這份研究數據顯示，表皮生長因子接受體突變的病患無論使用化療或標靶治療，在總體生存期的表現上並無差異。但另一方面，這份研究數據也清楚的證明，帶有表皮生長因子接受體突變的病患不論接受何種的第一線治療，要比那些不帶此突變的病患有更好的治療效果。
雖然在2008年歐洲腫瘤醫學會上所發表的愛瑞莎泛亞洲臨床研究初期研究數據顯示，病患使用愛瑞莎標靶治療在無惡化生存期方面有較佳的表現，但當時並沒有針對病患是否帶有表皮生長因子接受體突變進行區分，因此並不能完全涵蓋實際的狀況。 (對愛瑞莎標靶治療的個體反應率-- 突變者：無突變者= 71.2%：1.1%)
因此，在本研究報告中，楊志新醫師與他來自於台灣、中國、泰國及日本的同事們，篩選了1217名未接受過化療的末期非小細胞肺癌(肺腺癌)病患，隨機分為愛瑞莎(250mg/day)及卡鉑(AUC 5或6)/太平洋紫杉醇(200mg/m2)兩組，並評估他們的整體生存期。
研究結果顯示，帶有表皮生長因子接受體突變的病患，在無惡化生存期上的表現上，愛瑞莎標靶治療明顯高於化療病患(HR, 0.48; P < .0001)，但在整體生存期上並無明顯的差異。但研究結果也顯示，化療對於帶有表皮生長因子接受體突變的病患，較那些不帶有突變的病患有更好的反應率(47.3%對23.5%)。
楊志新醫師進一步解釋造成不同組別在整體生存期上無明顯差異的可能原因，楊醫師表示，在這項臨床研究中有很高比例的病患是接受多種不同的治療，比如說，在愛瑞莎標靶治療組中，有60%的病患在抗藥性產生後接受了化學治療，只有31%的病患是接受愛瑞莎的單一治療；而在化學治療組中，有51%的病患接受了第二階段的標靶治療，只有38%的病患是接受卡鉑/太平洋紫杉醇的單一治療。而這些接受不同治療的病患，可能影響了整體生存期的統計結果。
楊志新醫師補充說，表皮生長因子接受體酪胺酸激酶抑制劑(愛瑞莎、得舒緩等肺癌標靶藥物)對於特定的族群有較佳的治療效果，早已在這多研究中獲得證實，我們也早已知道在一些東亞人種中，尤其是那些不吸煙或吸煙極少的肺腺癌患者，愛瑞莎是有效的，而帶有這些特徵的族群亦顯示有較高的可能性是帶有表皮生長因子接受體突變，我們假設這個族群以標靶藥物作為第一線治療是有效的或至少與用化療藥物一樣有效，但接受標靶治療有較佳的耐受性並能獲得較好的生活品質。病患在接受化療時，會有比較高的風險會產生頭暈、嘔吐、掉髮及神經毒性，而在接受愛瑞莎治療時則會產生紅疹/膿疱、腹瀉及皮膚乾燥等副作用。
而從這份臨床研究結果中，我們建議表皮生長因子接受體突變檢測應列入非小細胞肺癌治療過程中的一個項目，楊醫師表示，這項檢測對於那些未曾接受過有效治療的末期非小細胞肺癌病患而言，尤其在選擇第一線治療方法時是非常重要的。
法國第十一大學醫學及腫瘤醫學系教授，同時也是這篇論文的審查者，Jean-Charles Soria醫師指出，病患是否帶有表皮生長因子接受體突變並不能作為決定先接受化療或先接受標靶治療的依據。但毋庸置疑的，這對於病患是否應主張以愛瑞莎作為第一線治療是有效的方法，與化療相比，愛瑞莎為口服藥物，有較能接受的藥物耐受性，能提供較佳的生活品質、並且與化療具有相同甚至更好的治療效果。
EGFR Mutations Give Survival Benefit in Lung Cancer
Roxanne Nelson
October 18, 2010 (Milan, Italy) — Patients with epidermal growth-factor receptor (EGFR) mutation-positive nonsmall-cell lung cancer (NSCLC) might have a survival advantage over those with EGFR mutation-negative disease.
Final data from the Iressa Pan-Asia Study (IPASS) showed improved overall survival in patients with EGFR mutation-positive NSCLC, whether they receive treatment with gefitinib (Iressa) or carboplatin/paclitaxel chemotherapy.
The data were presented here at the 35th European Society for Medical Oncology (ESMO) Congress.
However, in contrast to earlier findings, overall survival was similar in patients treated with gefitinib and those treated with carboplatin/paclitaxel. Even though preliminary results demonstrated a significant improvement in progression-free survival in patients treated with gefitinib, this did not translate into an overall survival advantage.
According to mature IPASS data, median overall survival for patients receiving gefitinib was 18.8 months, compared with 17.4 months for those receiving doublet chemotherapy (hazard ratio [HR], 0.90, 95% confidence interval [CI], 0.79 - 1.02; P = .11).
"It wasn't statistically significant — there wasn't any difference in overall survival time," said study author Chih-Hsin James Yang, MD, PhD, director of the Cancer Research Center, College of Medicine, National Taiwan University, in Taipei.
But the mature overall survival data clearly demonstrate that patients with EGFR mutation-positive tumors had better outcomes than those with EGFR mutation-negative tumors, regardless of the first-line treatment they received, Dr. Yang said.
The median overall survival for patients with EGFR mutation-positive NSCLC who received gefitinib was 21.6 months, compared with 21.9 months for those who received combination chemotherapy (HR, 1.002; 95% CI, 0.756 - 1.328; P = .990).
The median overall survival for patients with EGFR mutation-negative tumors was only 11.2 months for patients receiving gefitinib, compared with 12.7 months for those receiving combination chemotherapy (HR, 1.181; 95% CI, 0.857 - 1.628; P = .309).
Contrast With Earlier Data
Early results of the IPASS trial were first presented at the 2008 ESMO Congress and, as reported by Medscape Medical News at that time, showed superiority for gefitinib in progression-free survival. This was particularly true for patients with EGFR mutations, compared with those without mutations (objective response rate, 71.2% vs 1.1%).
Progression-free survival was significantly longer with gefitinib than with chemotherapy in patients with EGFR mutations (HR, 0.48; P < .0001), but chemotherapy produced a better response in patients with EGFR mutations than in those without them (47.3% vs 23.5%).
Gefitinib is currently licensed in the United States for use in the treatment of patients with locally advanced or metastatic NSCLC whose disease has progressed after first-line chemotherapy. Last year, gefitinib was approved by the European Commission for the treatment of adults with locally advanced or metastatic NSCLC with activating mutations of EGFR tyrosine kinase across all lines of therapy.
Several noncomparative studies have demonstrated that EGFR tyrosine kinase inhibitors have superior effectiveness in certain populations, Dr. Yang noted. "We know that gefitinib has activity in patients of East Asian origin with adenocarcinoma histology who have never smoked or who smoked very little."
Patients with these characteristics appear to have a higher incidence of EGFR mutations. "We hypothesized that a clinically selected group of patients with these characteristics treated with an EGFR tyrosine kinase inhibitor as first-line therapy would have efficacy as least as good as carboplatin/paclitaxel, with benefits in tolerability and quality of life," he explained.
High Degree of Crossover
In the IPASS study, Dr. Yang and colleagues from Taiwan, China, Thailand, and Japan randomized 1217 chemotherapy-naïve patients with advanced NSCLC (adenocarcinoma) to either gefitinib (250 mg/day) or carboplatin (AUC 5 or 6) plus paclitaxel (200 mg/m2), and conducted a preplanned evaluation of the secondary end point of overall survival.
There was a high percentage of crossover in the cohort, which Dr. Yang believes might be the reason for the lack of significant difference between the treatment groups. In the gefitinib group, 60% of patients received subsequent combination chemotherapy, whereas in the chemotherapy group, 51% received subsequent gefitinib or erlotinib treatment. Only 31% of patients in the gefitinib group and 38% in the carboplatin/paclitaxel group did not receive further treatment.
"The crossing over may have diluted the overall survival outcome," he said.
These data reinforce the need for EGFR mutation testing as a standard part of the treatment of NSCLC, Dr. Yang said, adding that "it is important to consider very carefully when choosing a first-line treatment for advanced nonsmall-cell lung cancer, as many patients in clinical practice will not receive further active treatments."
Patients receiving chemotherapy reported a higher incidence of nausea and vomiting, alopecia, and neurotoxicity; those receiving gefitinib reported more rash/acne, diarrhea, and dry skin.
Reasons for First-Line Gefitinib
Jean-Charles Soria, MD, PhD, pointed out that it is not the sequence of therapy that makes a difference in patients with EGFR mutations.
But it is useful, nonetheless, to test for EGFR mutations, explained Dr. Soria, professor of medicine and medical oncology at the Paris University XI, France, and discussant of the paper. "Front-line gefitinib in these patients can be advocated for several reasons," he said.
Compared with chemotherapy, gefitinib offers a better quality of life, oral availability of the drug, similar symptom-improvement rates, a more favorable tolerability profile, and even a higher chance of efficacy later in the course of the disease, he said.
The study was sponsored by AstraZeneca. Dr. Yang reports receiving honoraria and/or doing advisory board work for AstraZeneca, Pfizer, Roche, Merck Serono, Bayer, MSD, and Boehringer Ingelheim. Several of his coauthors report relationships with AstraZeneca, Boehringer Ingelheim, Merck Serono, Chugai Pharmaceutical Co., Daiichi Sankyo Co., Eli Lilly, Eisai, Bristol-Myers Squibb, Takeda, and Pfizer.
35th European Society for Medical Oncology (ESMO) Congress: Abstract LBA2. Presented October 11, 2010
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